1,4-benzothiazepine-1-oxide derivative and pharmaceutical composition utilizing the same

ABSTRACT

Provided are novel compound that is useful as a treatment agent or a prophylactic agent for cardiac failure, cardiac failure due to dystelectasis, left ventricular diastolic impairment, angina or cardiac infarct, hypertension, ischemic cardiac disease, and myocardial relaxation impairment recognized in cardiac failure, atrial fibrillation or ventricular arrhythmia, and a pharmaceutical composition containing the same. The invention pertains to a 1,4-benzothiazepine-1-oxide derivative represented by general formula [I] (In the formula, R represents a hydrogen atom or a hydroxyl group.) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same [I].

TECHNICAL FIELD

The present invention provides a 1,4-benzothiazepine-1-oxide derivativerepresented by the general formula [I] or a pharmaceutically acceptablesalt thereof, and a pharmaceutical composition comprising thereof.

BACKGROUND ART

The heart has a pumping mechanism consisting of periodic contraction andrelaxation functions in the myocardium, which provides blood to theinternal organs and tissues of the whole body through a process wherethe blood is constantly circulating and returning to the heart. Thisprocess is a constant, periodic action in which the myocardium issupplied the necessary oxygen and nutrition from coronary circulation ofthe right and left coronary arteries. In a normal functioningmyocardium, the oxygen supply and consumption are maintained in thehomeostatic state.

When the myocardium is unable to contract and relax properly resultingin damage to the pumping function, congestion in the general organs andtissues is induced and heart failure occurs. During heart failure,activation of the sympathetic nervous system occurs, as well asincreased levels of norepinephrine in the blood, leading to an increasein heart rate.

Presently, there are drug treatments for heart failure such asβ-blockers that decrease heart rate, and lessen the contractility force,resulting in a decrease of oxygen consumption required from themyocardium. However, at high doses, β-blockers increase the risk forheart failure and must be used or administered with caution.

The myocardium contracts and relaxes regularly and periodically. Thiscardiac cycle is divided into two phases; systolic phase and diastolicphase. The systolic phase is from the mitral valve closure to the aorticvalve closure and the diastolic phase is from the aortic valve closureto the mitral valve closure. Moreover, diastolic phase has 4 stages;isovolumic relaxation, rapid left ventricular filling, slow leftventricular filling, and atrial contraction. In the latter 3 stagesamong the 4 stages; rapid left ventricular filling, slow leftventricular filling, and atrial contraction, the ventricular myocardiumexpands more and blood inflow from atrium to ventricle occurs. Thediastolic function of the ventricle has important significance on thecardiac function. When myocardial expansion is impaired, the bloodinflow to the ventricle is hindered and then heart failure, especiallyheart failure due to diastolic dysfunction, occurs. Moreover, bloodflows from the coronary artery into the myocardial tissues duringdiastolic phase, which is different from that of other organs. Thediastolic blood flow is remarkably more from the left coronary arterythan the right coronary artery. Therefore, the diastolic impairment ofleft ventricle induces disturbance of coronary flow into the leftventricular myocardial tissues, generates myocardial ischemia, and as aresult aggravates heart failure due to diastolic dysfunction.

Moreover, left ventricular diastolic impairment occurs in elderly peopleand inpatients with hypertension and cardiac hypertrophy even withoutthe presence of heart failure. Left ventricular diastolic impairmentscan easily be diagnosed using Doppler echocardiography. Some patientswith left ventricular diastolic impairment complain of symptomsincluding fatigue, shortness of breath, chest discomfort and chest pain.During prolongation of left ventricular diastolic impairment, impairmentof the cardiomyocytes and fibrosis in the myocardium eventually induceheart failure.

To maintain normal functions of the heart, the appropriate amounts ofoxygen and nutrients required are supplied to the myocardium throughcoronary perfusion by the left and right coronary arteries. Thecontraction and relaxation of the myocardium requires the oxygen andnutrients to function properly.

The drugs used to dilate the coronary arteries leads to an increase ofoxygen supply to the myocardium, thus reducing the risk of myocardialischemia. Myocardial oxygen consumption is determined by the heart rateand cardiac contractility, and that drug decreases oxygen consumption byreducing heart rate and myocardial contractility, lowering the risk ofmyocardial ischemia. A drug capable of dilating the coronary arterycombined with decreasing heart rate and contractility, is a treatmentagent or a prophylactic agent for ischemic heart disease, such as anginapectoris and myocardial infarction.

Heart failure is divided into systolic failure and diastolic failure. Insystolic failure, the left ventricular minimum diastolic pressure andleft ventricular diastolic pressure both increase, therefore the drugreinforcing the left ventricular diastolic function is comprised of anagent that leads to the improvement of systolic failure.

Furthermore, a drug is a treatment agent for angina pectoris andmyocardial infarction because it dilates the coronary artery and thenenhances the oxygen supply to the myocardium. The consumption of oxygenfrom the myocardium is dependent upon the contractility force and heartrate. It is comprised of a drug that is a prophylactic agent forischemic heart disease, such as angina pectoris and myocardialinfarction. The β-blocker is a treatment agent for angina pectoris andmyocardial infarction, however, it does not have the effect to dilatethe coronary arteries or increase left ventricular diastolic function.

A drug, reinforcing the left ventricular diastolic function, decreasingheart rate, increasing reduction of contractility, combined withdilation of the coronary artery, is comprised of a treatment agent or aprophylactic agent for heart failure due to diastolic dysfunction.

Moreover, the relaxant function in the heart is equally important assystolic function and diastolic function. Relaxation is the maincomponent in the first stage among the four stages of the diastolicphase; the function of isovolumic relaxation, which is able to beestimated using the maximal negative first derivative of the leftventricular pressure (−dP/dt) and the disturbance of relaxant functionis able to be detected in the left ventricular wall motion by usingDoppler echocardiography.

Heart failure is induced by numerous complexities such as myocardialsystolic impairment, relaxation impairment, or diastolic impairment.Diastolic heart failure is generally formed with the complexities ofdiastolic impairment and relaxant impairment. Relaxant impairment isrecognized in ischemic heart disease, atrial fibrillation, andventricular arrhythmia and worsens severely, resulting in decreasedcardiac contractility. The improvement of myocardial relaxant functionis essential for the treatment of ischemic heart disease, atrialfibrillation, and ventricular arrhythmia. Relaxation impairment worsensseverely and “Rigor” occurs, not allowing relaxation. Deterioration ofrelaxation impairment leads to heart failure.

Myocardial relaxation impairment is recognized in ischemic heartdisease, hypertensive heart disease, heart failure, atrial fibrillation,and ventricular arrhythmia. There are still no drugs that allow arelaxant effect on the myocardium. Catecholamines such as epinephrineand norepinephrine (NE) stimulate to take the calcium uptake of thesarcoplasmic reticulum and promote myocardial relaxation. However, thosesubstrates also increase heart rate and blood pressure, resulting inenhancement of myocardial oxygen consumption. It is difficult to use thetreatment agents for the disease mentioned. The ideal drug is amyocardial relaxant which promotes myocardial relaxation withoutchanging the heart rate. It is an agent that does not change heart rateand accelerates myocardial relaxation, and an agent which can improveischemic heart disease, hypertensive heart disease, heart failure,atrial fibrillation, and ventricular arrhythmia, and cardiac function.

Blood pressure is determined by cardiac output, peripheral bloodresistance, circulation blood volume, and blood viscosity.Norepinephrine increases the peripheral vascular resistance and raisesblood pressure. It is a treatment agent or a prophylactic agent used todecrease blood pressure for hypertension due to norepinephrine-loadedhypertension.

Meanwhile,4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepineand derivatives thereof have been reported to have the effectivecompounds which inhibit myocardial necrosis including kinetic cell death(KD) and acute myocardial infarction without cardiac suppressive effects(Patent Documents 1 and 2). There have been many reports regarding itseffectiveness on atrial fibrillation as well as its anticancerproperties, for example, use for the treatment of atrial fibrillation(Patent Document 3), enhancement of anti-cancer agents for the treatmentof cancer (Patent Document 4), use for the improvement or stabilizationof the ryanodine receptor function, Ca²⁺ leak from the sarcoplasmicreticulum (Patent Document 5), muscle relaxation accelerator, treatmentfor left ventricular relaxation disturbance, treatment for anginapectoris, treatment for acute pulmonary emphysema, for improvement ofmicrocirculation blood flow, for hypertension, for ventriculartachycardia and torsades de pointes (Patent Document 6).

PRIOR ART DOCUMENTS Patent Documents

Patent Document 1: Japanese Patent Application Laid-Open (JP-A) No.4-230681

Patent Document 2: WO 92/12148

Patent Document 3: JP-A No. 2000-247889

Patent Document 4: JP-A No. 2001-31571

Patent Document 5: JP-A 2003-95977

Patent Document 6: WO 2005/105793

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention provides a novel pharmaceutical composition fortreatment agent enhancing cardiac relaxation and improving myocardialrelaxation impairment, and a therapeutic agent of relaxation of thevascular smooth muscle and hypertension by decreasing blood pressure.Moreover, it accelerates relaxation of skeletal muscle and uterinesmooth muscle and provides a compound as a treatment agent or aprophylactic agent for muscle hypertonia and miscarriage.

Furthermore, the present invention provides a novel compound that isuseful as a treatment agent or a pharmaceutical compound containing thesame for improving cardiac relaxation without changing heart rate.

Means for Solving the Problems

The present inventor has been researching several pharmacologicaleffects of4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepineand derivatives thereof. These compounds have been reported to haveextremely significant pharmacological effects in the citations listedabove. The present inventor urged more research and found that itssulfur (S)-oxide derivatives have similar effects as the basic freecompound and specific pharmacological effects not found in the basicfree compound.

That is, the present invention provides a novel1,4-benzothiazepine-1-oxide derivative represented by the followinggeneral formula [I]:

(wherein, R is a hydrogen atom or a hydroxyl group.) and apharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical compositioncomprising the 1,4-benzothiazepine-1-oxide derivative or apharmacologically acceptable salt thereof, and a pharmacologicallyacceptable carrier.

The present invention includes contents explained in detail below.

-   (1) A 1,4-benzothiazepine-1-oxide derivative represented by the    following general formula [I]:

(wherein, R is a hydrogen atom or a hydroxyl group.) and apharmaceutically acceptable salt thereof.

-   (2) The 1,4-benzothiazepine-1-oxide derivative according to (1),    wherein the pharmaceutically acceptable salt of    1,4-benzothiazepine-1-oxide-derivative in an oxalate.-   (3) A pharmaceutical composition comprising the    1,4-benzothiazepine-1-oxide derivative according to (1) or (2), or    the pharmaceutically acceptable salt thereof and the    pharmacologically acceptable carrier.-   (4) The pharmaceutical composition according to (3), wherein the    pharmaceutical composition is a treatment agent or a prophylactic    agent for cardiac disease and hypertension.-   (5) The pharmaceutical composition according to (4), wherein the    cardiac disease includes cardiac failure, angina pectoris or    myocardial infarction.-   (6) The pharmaceutical composition according to (5), wherein cardiac    failure includes left ventricular diastolic impairment or cardiac    relaxation impairment.-   (7) The pharmaceutical composition according to (4), wherein the    hypertension is due to the effect of decreasing blood pressure    during high blood pressure.-   (8) The pharmaceutical composition according to (3), wherein the    pharmaceutical composition is a treatment agent or a prophylactic    agent for myocardial relaxation impairments due to complications of    ischemic heart disease, hypertension cardiac disease, heart failure,    atrial fibrillation, and ventricular arrhythmia, by promoting    acceleration of myocardial relaxation without changing heart rate.-   (9) A pharmaceutical composition according to any one of (3) to (8),    wherein the 1,4-benzothiazepine-1-oxide derivative or a    pharmaceutically acceptable salt thereof is generated in vivo by    administering a 1,4-benzothiazepine derivative or a pharmaceutically    acceptable salt thereof represented by the following formula [II]:

(wherein, R is a hydrogen atom or a hydroxyl group.) to a subject as amaternal compound of the 1,4-benzothiazepine derivative represented bythe following formula [I].

-   (10) A method of producing a 1,4-benzothiazepine-1-oxide derivative    represented by the following general formula [I]:

(wherein, R is a hydrogen atom or a hydroxyl group.) and apharmaceutically acceptable salt thereof comprising a step by oxidizinga 1,4-benzothiazepine derivative represented by the followingformula[II]:

(wherein, R is a hydrogen atom or a hydroxyl group.).

-   (11) A method of producing a 1,4-benzothiazepine derivative    according to (10), wherein the oxidation carries out in the presence    of peracid as a oxidation agent.-   (12) A use of a 1,4-benzothiazepine-1-oxide derivative or a    pharmaceutically acceptable salt thereof represented by the general    formula [I] described above to produce a treatment agent or a    prophylactic agent for cardiac disease or hypertension.-   (13) A use of a 1,4-benzothiazepine-1-oxide derivative or a    pharmaceutically acceptable salt thereof represented by the general    formula [I] described above to produce a treatment agent or a    prophylactic agent for cardiac failure due to myocardial relaxation    impairment.-   (14) A use according to (12) or (13), wherein a    1,4-benzothiazepine-1-oxide derivative or a pharmaceutically    acceptable salt thereof represented by the general formula [I]    described above, is generated in vivo by administering a    1,4-benzothiazepine derivative or a pharmaceutically acceptable salt    thereof represented by the general formula [II] described above.-   (15) A 1,4-benzothiazepine-1-oxide derivative or a pharmaceutically    acceptable salt thereof represented by the general formula [I]    described above to be used for a treatment agent or a prophylactic    agent for cardiac disease or hypertension.-   (16) A 1,4-benzothiazepine-1-oxide derivative or a pharmaceutically    acceptable salt thereof represented by the general formula [I]    described above to be used for a treatment agent or a prophylactic    agent for cardiac failure due to myocardial relaxation impairment.-   (17) A method of treatment of cardiac disease and hypertension by    administrating an effective dose of a pharmaceutical composition    comprising of a 1,4-benzothiazepine-1-oxide derivative or a    pharmaceutically acceptable salt thereof represented by the general    formula [I] described above to a patient with cardiac disease or    hypertension.-   (18) A method of treatment of cardiac failure due to myocardial    relaxation impairment by administrating an effective dose of a    pharmaceutical composition comprising of a    1,4-benzothiazepine-1-oxide derivative or a pharmaceutically    acceptable salt thereof represented by the general formula [I] to a    patient with cardiac failure due to myocardial relaxation    impairment.

While the compound of the present invention represented by generalformula [I] or a salt thereof is thought to be metabolized in vivo fromthe general formula [II] of the basic compound or a salt thereof, thepresent inventor has produced the compound of the general formula [I],discussed in detail the properties, and firstly found that the concernedcompound represented by the general formula [I] possesses usefulpharmacological effects.

Moreover, the compound of the present invention represented by thegeneral formula [I] or a salt thereof is different from the basiccompound represented by the general formula [II] or a salt thereof,regulates the cardiac relaxant function without increasing the heartrate, and is considered to have different pharmacological effectscompared to the basic compound represented by the general formula [II]or a salt thereof.

It is difficult even for the cardiologist to know how to treat diseasesusing β-blockers because it reduces myocardial contractility anddecreases heart rate. It is generally recommended to use treatment atlow doses since administration at a high dose is dangerous. The Ca²⁺antagonist dilates the coronary artery and rapidly decreases bloodpressure and it is also generally recommended for treatment at low dosessince administration at a high dose is dangerous. For safety concernsand requirements, mild agents are best used for dilatation of thecoronary artery, suppressive effects on cardiac contraction, anddecrease in heart rate.

The present inventor has been found that the compound of the presentinvention represented by the general formula [I] or the salt thereofpossesses the ability to increase left ventricular diastolic function,dilate the coronary artery, reduce myocardial contractility, mildlydecrease heart rate, and is useful for cardiac failure, cardiac failuredue to diastolic dysfunction, left ventricular diastolic impairment,angina pectoris, or myocardial infarction. Moreover, the compound of thepresent invention has been found to be useful as a treatment agent toimprove the cardiac relaxant function without changing heart rate forischemic heart disease, hypertensive heart disease, cardiac failure,atrial fibrillation, and ventricular arrhythmia.

And, it has been found that the compound of the present inventionrepresented by the general formula [I] or a salt thereof has the mildeffect to improve myocardial diastolic function, dilate the coronaryarteries, decrease heart rate and decrease cardiac contractility.

The present inventor discovered that the compound of the presentinvention possesses useful effects for improvement of left ventriculardiastolic function and inhibits norepinephrine-induced left ventriculardiastolic impairment.

The present invention provides the compound of the present invention asa useful agent to improve left ventricular diastolic function, cardiacfailure and diastolic failure, wherein physical signs of an increase inleft ventricular minimum diastolic pressure and left ventricularend-pressure are present.

The present invention provides a useful agent of treatment andprevention wherein the compound of the present invention is administeredto the elder person and patients with hypertension and cardiachypertrophy, and for the improvement of left ventricular diastolicimpairment in patients with physical signs of left ventricular diastolicimpairment. In the present invention, the compound of the presentinvention is provided as a safe, useful agent to patients of anginapectoris with significant constriction of coronary artery and myocardialinfarction. Moreover, the present invention is provided by the compoundof the present invention as a useful treatment agent or a prophylacticagent to improve myocardial relaxation impairment combined with ischemicheart disease, hypertensive heart disease, cardiac failure, atrialfibrillation, and ventricular arrhythmia.

Therefore, the present invention provides a novel compound which isuseful, and a pharmaceutical compound containing these compounds of thepresent invention.

Moreover, the compound of the present invention represented by thegeneral formula [I] or a salt thereof is considered the basic compoundrepresented by the general formula [II] or the metabolite of the salt invivo. So, the pharmaceutical compound of the present invention is ableto use the basic compound represented by the general formula [II] or asalt thereof as the pro-drug instead the present invention representedgeneral formula [I] and the basic compound represented by the generalformula [II].

Effects of the Invention

The compound of the present invention itself possesses the effects toimprove myocardial diastolic function, to mildly dilate the coronaryartery, decrease heart rate, and increase the oxygen supply bydecreasing myocardial oxygen consumption. Therefore, the presentinvention provides a novel pharmaceutical compound that is useful as atreatment agent and a prophylactic agent in a safe and desirable mannerfor the elder person and patients with hypertension and cardiachypertrophy, patients of cardiac failure due to diastolic failure,angina pectoris and myocardial infarction, and for those who have badprognoses and are conventionally difficult to treat.

In addition, the compound of the present invention possesses the abilityto improve cardiac relaxation without changing heart rate and is usefulfor myocardial relaxant impairment. The compound of the presentinvention is useful as a treatment agent or a prophylactic agent forhypertension. Moreover, the compound of the present invention is usefulas a treatment agent or a prophylactic agent for improving myocardialrelaxation impairment combined with ischemic heart disease, hypertensiveheart disease, cardiac failure, atrial fibrillation, and ventriculararrhythmia.

The present pharmaceutical compound may be administered through oral,sublingual, transdermal patch, and intravenous methods, or infused intothe coronary artery to eliminate spasms after inducing itdiagnostically, and as well as treatment and prevention of coronaryspasms.

Moreover, the compound of the present invention is able to allow lowerdosages of β-blockers and Ca²⁺ antagonists for treatment or preventionof angina pectoris, especially myocardial ischemia on angina pectoris,and for treatment or prevention against cardiac failure, especiallycardiac failure due to diastolic failure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing a comparison of change in heart rate(beats/min) before and after administration of the compounds of thepresent invention [III], and its basic compound of general formula [II](R═H).

FIG. 2 is a graph showing a comparison of change in left ventricularpressure (mmHg) before and after administration of the compounds of thepresent invention [III], and its basic compound of general formula [II](R═H).

FIG. 3 is a graph showing a comparison of change in cardiac diastolicrelaxation function (mmHg/sec) before and after administration of thecompounds of the present invention [III], and its basic compound ofgeneral formula [II] (R═H).

FIG. 4 is a graph showing the comparison of change in left ventricularpressure before and after administration of the present invention [III]on norepinephrine-induced hypertension.

MODES FOR CARRYING OUT THE INVENTION

The present invention provides a 1,4-benzothiazepine-1-oxide derivativerepresented by the following general formula [I] or a pharmaceuticallyacceptable salt thereof:

(wherein, R is a hydrogen atom or a hydroxyl group.) The preferredexamples of the present invention include a4-[3-4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxideor a pharmaceutically acceptable salt thereof represented by thefollowing formula [III]:

and a4-{3-[4-(4-hydroxybenzyl)piperadin-1-yl]propionyl}-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxiderepresented by the following formula [IV] or a pharmaceuticallyacceptable salt thereof.

The compound of the present invention contains the basic nitrogen atomat positions where it is able to form the addition of acid salts.Formations of the addition of acid salts are not particularly limited,as long as they are of pharmaceutically acceptable material. Thecompound of the present invention favors the addition of specific acidsalts such as inorganic acid salts; hydrochloride, hydrobromate,sulfate, phosphate, nitrate, and the addition of organic acid salts;oxalate, acetate, propionate, succinate, glycolate, lactate, malate,tartrate, citrate, maleic acid salts, fumarate, methanesulfonate,benzenesulfonanate, p-toluenesulfonate, and ascorbate. Hydrate is also agood solvent for the compound of the present invention or the acid saltaddition.

In the compound of the present invention, the heterocyclic sulfur (S)and oxygen (O) bond, that is, forms the polar atomic group indicated bystrong electric negativity and is also the coordinate bond. Regardingthe sulfur and oxygen bond, the coordinate bond can be represented withan arrow; “heterocyclic sulfur (S)→oxygen (O)” and this coordinated bondcan be represented as “heterocyclic S⁺—O⁻”.

The compound of the present invention represented by the general formula[I] is able to be produced by the oxidation by the proper oxidationagents of the compound represented by the general formula [II].Peracids, for example, peracetic acid, perbenzoic acid, andmeta-chloroperoxybenzoic acid (mCPBA) can be used as the oxidationagents. Preferred solvents are halogenated hydrocarbon such as methylenechloride and chloroform may be used. The reaction temperature ispreferably maintained low, between 0-5° C., to prevent oxidation to thefinal sulfonation. The objective material can be isolated and purifiedfrom the reaction mixture by the known steps of isolation andpurification using the extractive procedure, chromatography anddistillation.

For example, the compound,4-[3-4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxiderepresented by the formula [III] of the present invention is able to beproduced as shown in the following procedure:

by an oxidation of the heterocyclic sulfur in the4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepineof the compound [V] by the oxidant, for example,meta-chloroperoxybenzoic acid (mCPBA) in a chloroform (CHCl₃) solvent.

The compound of the present invention,3-4-benzylpiperidin-1-yl)propionyl-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide,which is produced by an oxidation of the hydrochloride salt representedby formula [V] by the oxidant, isolated by silica gel chromatographyusing chloroform-methanol as a solvent, followed by removed the solventfrom the chloroform-methanol solution by azeotropic distillation, andfinally removed by the residual solvent in argon. The purity of compoundpresented by formula [III], thus obtained is 90% or higher, and amolecular weight (mw) of the compound is 440.61. The compound isamorphous, stable against exposure of oxygen, humidity, acid and alkaliat room temperature, is easily dissolved in ethanol and dimethysulfoxide(DMSO), and irritating to the skin. The oxalate salt of the compound[III] of the present invention has a mw of 530.65, the purity is 90% orhigher. The salt is solid with melting point at 167-168° C., and is ableto be dissolved in water, ethanol, DMSO. The compound has stereoisomersin the amide form, is confirmed to exist at the rate of about 2:3 in ofamide parts using ¹H-NMR analysis at room temperature.

The compound4-{3-[4-(4-hydroxybenzyl)piperadin-1-yl]propionyl}-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxiderepresented by the formula [IV] or a pharmaceutically acceptable saltthereof is produced by preserving a hydroxyl group in necessarysituations, by a similar oxidative reaction. The basic1,4-benzothiazepine derivative was administered to either a rat or dog,then the urine and excrement was obtained, adding water forhomogenization. The compound was isolated from the obtained supernatantby high performance liquid chromatography (HPLC) using a reverse columnwith silica gel (ODS) chemically bounded with octadecyl group; andgradient isolations as a mobile phase: solution A is water with 0.1%trifluoroacetic acid (TFA) and solution B is acetonitrile with 0.1%trifluoroacetic acid (TFA). The retention time was about 19-22 minutes.MS (m/z): 457. The compound [III] was isolated using HPLC with gradientisolation using the procedure similar to the compound [IV] of thepresent invention and obtained within 27-30 minutes of the retentiontime.

The compound of the present invention represented by the formula [I] ora salt thereof is useful as a treatment agent or a prophylactic agentfor heart disease, including heart failure, angina pectoris, myocardialinfarction, or hypertension, and moreover, is useful as a treatmentagent or a prophylactic agent for heart failure due to diastolicdysfunction, left ventricular relaxation impairment, improving thecardiac diastolic function and improving ischemic heart disease,hypertensive heart disease, cardiac failure, atrial fibrillation, andventricular arrhythmia without changing the heart rate.

Therefore, the compound of the present invention represented by theformula [I] or a salt thereof is used as an active ingredient ofpharmaceutical composition. The pharmaceutical composition of thepresent invention is administered orally and sublingually,transdermally, intravenously, and injected into the coronary artery toprevent coronary artery spasms after inducing it diagnostically, as wellas treatment and prevention of coronary spasms. Moreover, the treatmentand prevention of the compound of the present invention allows adecrease in the dosage of treatments using β-blockers and Ca²⁺antagonists.

The active ingredient of the present pharmaceutical composition isobtained from the maternal compound represented by the general formula[II] or a salt thereof in vivo as the pro-drug as described in theexperimental data. Therefore, the active ingredient in thepharmaceutical composition of the present invention may be the compoundrepresented by the general formula [II] or a salt thereof as thepro-drug instead of the compound represented by the formula [I] or asalt thereof. The compound of the present invention represented by thegeneral formula [I] is obtained in vivo as the metabolite of the basiccompound of the present invention represented by the general formula[II] or a salt thereof, and is able to be used as the pro-drug asdescribed in the experimental data.

Solid dosage forms for oral administration of the present inventioninclude tablet, pill, powder and granule forms. The solid compound canbe produced under a standard procedure using the active materialcombined with an inactive dilute agent, dispersion agent, or absorbentsuch as lactate, mannitol, glucose, hydropropyl cellulose,slightly-crystalline cellulose, starch, polyvinylpyrolidone, magnesiummetasilicic aluminate, or silicic anhydride powder.

For preparation of solid dosage forms such as a tablet or pill, it isrecommended to use a coating membrane consisting of a gastricacid-soluble or an intestine-soluble material substance such as sucrose,gelatin, hydroxypropyl-cellulose, hydroxymethyl cellulose phthalate, ora two-layer coating membrane. Moreover, it is able to be made from acapsule such as gelatin or ethylcellulose.

Liquid dosage forms for oral administration of the present inventioninclude pharmaceutically acceptable emulsions, solutions, suspensions,syrups, or elixir agents. Dilating agents, such as distilled water,ethanol, vegetable oil or other emulsions are best recommended to bemixed with subsidiary agents aside from dilating agents such as wettingagents, suspending agents, sweetening agents, flavoring agents, aromaticagents, or preservatives for this compound.

Non-oral injection preparations of the compound include abacterial orsterile water, non-aqueous solution, emulsifying agents and suspendingagents. Aqueous solutions, solutions, and emulsions used for theinjection include distilled water, physiological salt solutions,cyclodextrin and derivatives thereof, organic amines such astriethanolamine, diethanolamine, monoethanolamine, andtriethylethylamine, or inorganic alkali solutions.

In the case of producing a water-soluble agent, it is better to usevegetable oils such as propylene-glycol, polyethylene-glycol or oliveoil, and an alcohol such as ethanol. Soluble agents includesurface-active agents such as polyoxyethyl consolidated castor oil,sucrose-fatty acid-esters (formation of mixed micelle) or lecithin, andlecithin in aqueous solution (liposomal formation). The emulsificationagent is able to be made from the water-insoluble solutions such asvegetable oils, lecithins, polyoxyethyl consolidated castor oil,polyoxyethylene, or polyoxypropylene-glycol.

The compound of the present invention represented by the general formula[I] or a salt thereof, or the compound of the pro-drug represented bythe general formula [II] or a salt thereof is able to be administeredbetween 0.1 mg to 1 g, at the proper range of 1 mg-1 g or 0.1 mg-0.5 g,once to several times a day through oral or non-oral methods. However,the methods of administration, treatment time and effects of treatmentmay vary based on differences in age, body weight, and symptoms.

The present invention is described in practice 1 below, which is setforth to aid in the explanation and understanding of the invention, withnon-limiting preferred embodiments of the invention.

EXAMPLE 1 Production of4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxiderepresented by the formula [III] of the present invention

30.0 g of4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepinehydrochloride represented by the formula [V] and 800 ml of chloroform(CHCl₃) as a solvent were added to a reactor and stirred at roomtemperature until dissolved. Then, the reaction mixture was cooled to0-1° C. by ice-cold water bath. Then 14.0 g of meta-chloroperoxybenzoicacid (mCPBA) in 600 ml of CHCl₃ solution was gradually added by dropwiseto the solution within 110 minutes while maintaining the reactiontemperature. After the dropping, the mixture was stirred for about 20minutes at 0-1° C.

Then, 4.14 g of Na₂SO₃ in 200 ml of H₂O solution was added to thereaction mixture by dropwise in 1 minute at 0-5° C., and stirred for 10minutes at 0-5° C. Subsequently, sodium hydroxide (NaOH) solution (1mol/L) was dropwised for 1 minute while maintaining at a cooltemperature. After the dropwise, the reaction mixture was stirred for15-20 minutes at 0-5° C. After the reaction, organic layer wasseparated, washed the remaining aqueous layer by 600 ml chloroform(CHCl₃). The two organic layers were combined and washed with 200 ml ofH₂O once and then washed with 200 ml of saturated NaCl solution once.The organic layer was dried with anhydrate Na₂SO₄ and concentrated underreduced pressure.

The residue was purified by silica gel chromatography using ethanol. 13g of the objective material was obtained as a viscous amorphous or oil.

IR (cm⁻¹) : 3452, 2919, 1643, 1594, 1022

¹H-NMR (CDCl₃ 300 MHZ): δ1.1-2.95(17H, m), 3.78(3H, s), 3.86-4.16(2H,m), 4.65(2H, s), 6.8-7.65(8H, m)

MS (FD-MS): 441 (M⁺)

EXAMPLE 2 Production of the Compound [IV] of the Present Invention

Using three male Sprague Dawley rats, 0.3 mg/kg of a maternal compoundof the chemical compound [IV] was intravenously administered. Theirurine and excrement were obtained 24 hours after administration. Waterwas added to the excrement for homogenization. Then the pooled samplesfor the three cases were treated for measurement.

2g of the pooled excrement sample was mixed with 4 ml of acetonitrile,stirred, centrifuged and the supernatant was extracted. The obtainedsupernatant was concentrated and dried at 40° C. under a stream ofnitrogen gas. The dried material was dissolved in acetonitrile andwater. The resulting solution was analyzed using liquid chromatographymass spectrometry (LC/MS) and the excluding material was obtained within21-22 minutes of the retention time. LC/MS (m/z): 457.

The urine sample was centrifuged and then the supernatant was analyzedusing LC/MS. The excluding material was obtained within 21-22 minutes ofthe retention time. LC/MS (m/z): 457.

EXAMPLE 3 Experiment 1 Effect of the Compound [III] of the PresentInvention for LV Diastolic Function in Normal Rat

(1) After breeding for 1 week, male Wistar rats were anesthetized with3% isoflurane inhalation, followed by an insertion of a tube in thetrachea and respiration subsequently controlled with an artificialventilator using 1.7% isoflurane for maintained anesthetization. Amicrometer-tipped pressure catheter (Manufactured by 2F, MillarInstruments) was inserted from the right common carotid artery into theleft ventricle (LV) and a polyethylene catheter (SP10) was inserted intothe right femoral vein for the compound of the present invention orphysiological salt solution (PSS) injections. After confirming stablehemodynamics for 10 minutes, LV minimum diastolic pressure and LVend-diastolic pressure was counted every minute. The compound [III] (0.1mg/kg/min) of the present invention or PSS was infused at 16.6 μL/minfor 10 minutes in the test and control groups, respectively.

LV minimum diastolic pressure and LV end-diastolic pressure was countedevery minute for 20 heart beats before and after administration of thecompound. LV minimum diastolic pressure and LV end-diastolic pressurebefore administration was set at 100% and the data of each afteradministration was calculated as a percentage change from beforeadministration. Data is shown as mean and standard deviation. Theresults are shown in Table 1 and 2.

TABLE 1 Measurement of LV minimum diastolic pressure and end-diastolicpressure before and after administration of physiological salt solution(PSS) Before After administration administration of PSS of PSS LVminimum diastolic pressure 100% 101.6 ± 4.5% LV end-diastolic pressure100% 102.0 ± 5.2%

LV minimum diastolic pressure and LV diastolic end-diastolic pressuredid not decrease after the administration of PSS.

LV minimum diastolic pressure and LV diastolic end-diastolic pressurebefore and after the compound [III] of the present invention isindicated in Table 2.

TABLE 2 Measurement of LV minimum diastolic pressure and end-diastolicpressure before and after administration of the compound [III] of thepresent invention Before After administration administration of compound[III] of compound [III] LV minimum diastolic 100% 76.0 ± 5.2% pressureLV end-diastolic 100% 78.4 ± 6.6% pressure

LV minimum diastolic pressure and LV diastolic end-diastolic pressure innormal rats clearly decreased after administration of compound [III].From the result, the compound of the present invention possesses theability to improve LV diastolic dysfunction.

EXAMPLE 4 Experiment 2. Effect of LV Diastolic Dysfunction of theCompound [III] of the Present Invention for the Chronic Infarct Rat

Male Wistar rats were used. After induction of anesthesia with 3%isoflurane inhalation, a polyethylene tube was inserted into thetrachea. Respiration was subsequently controlled with an artificialventilator with maintenance of anesthesia using 1.7% isoflurane. Thechest was opened at the left third intercostals space and thepericardial membrane was incised. The left anterior descending coronaryartery (LAD) was completely ligated with silk string (6.0, Ethicon) inthe infarction group. Following this procedure, the chest wasimmediately closed, the inserted tube in the trachea was removed, andsubjects returned to the breeding room after arousal.

Two months after operation, animals were again anesthetized andintubated as described above. A micronanometer-tipped pressure catheter(2F, Millar Instruments) was inserted into the right common carotidartery into the left ventricle (LV) and a polyethylene catheter (SP10)for solution injection was inserted from the right femoral vein toinfuse the physiological salt solution (PSS) or test compound solutions.After confirming stable hemodynamics for 10 minutes, 20 μg/kg/min ofnorepinephrine was infused for 30 minutes in the chronic infarctiongroup. The results of the production of norepinephrine-induceddysfunction in chronic infarction are indicated in Table 3. Theinvention compound [III] (0.1 mg/kg/min) and PSS were infused for 10minutes after 20 minutes of administration of norepinephrine at 16.6μL/min for test and control groups, respectively. LV minimum diastolicpressure and LV end-diastolic pressure was counted every minute for 20heart beats. The area of myocardial infarction (infarction size) in ratswas estimated using the modified method of Sandmann et al (J CardiovascPharmacol 2000; 37; 64-77.) for administration of the compound of thepresent invention and PSS. That is, the infarct size (%) was estimatedusing the followed formula:

${{myocardial}\mspace{14mu} {infarction}\mspace{14mu} {area}\mspace{14mu} (\%)} = {\left\lceil \frac{\left( \frac{{{epicardial}\mspace{14mu} {infarct}\mspace{14mu} {length}} + {{endocardial}\mspace{14mu} {infarct}\mspace{14mu} {length}}}{2} \right)}{\left( \frac{\begin{matrix}{{{total}\mspace{14mu} {LV}\mspace{14mu} {epicardial}\mspace{14mu} {circumference}} +} \\{{total}\mspace{14mu} {LV}\mspace{14mu} {endocardial}\mspace{14mu} {circumference}}\end{matrix}}{2} \right)} \right\rceil \times 100}$

The infarct size in the invention compound group and PSS group werealmost of similar sizes at 24% and 26%, respectively.

LV minimum diastolic pressure and LV end-diastolic pressure beforeadministration was set: at 100% and the data of each afteradministration was calculated as a percentage change from beforeadministration. Data is shown as means and standard error. The followingresults are shown in Table 4 (control) and Table 5 (the compound),respectively.

TABLE 3 Production of norepinephrine-induced diastolic dysfunction inchronic infarction Before After administration of administration of(mmHg) Norepinephrine Norepinephrine LV minimum diastolic 4.5 ± 0.8 18.5± 1.2 pressure LV end-diastolic 6.5 ± 0.7 25.8 ± 1.1 pressure

After the administration of norepinephrine, LV minimum diastolicpressure and LV end-diastolic pressure clearly increased in chronicinfarction rats, which indicated occurrence of the diastolic impairment.

TABLE 4 Measurement before and after administration of physiologicalsalt solution (PSS) Before After administration administration of PSS ofPSS LV minimum diastolic pressure 100% 104.6 ± 4.8% LV end-diastolicpressure 100% 105.0 ± 5.1%

For norepinephrine-induced LV diastolic dysfunction in chronic infarctrats, LV minimum diastolic pressure and LV end-diastolic pressure didnot decrease after infusion of PSS.

TABLE 5 Measurement before and after administration chemical compound[III] of the present invention Before After administrationadministration of compound [III] of compound [III] LV minimum diastolic100% 76.0 ± 5.2% pressure LV end-diastolic 100% 78.4 ± 6.6% pressure

LV diastolic impairment was induced by a norepinephrine infusion tochronic infarct rats and LV minimum diastolic pressure and LVend-diastolic pressure clearly decreased after infusion of compound[III]. From the result, the compound of the present invention indicatesan ability to improve LV diastolic impairment.

As shown above, the results of Practice 3, Practice 4, Experiment 1 andExperiment 2 indicate improvement from the present invention chemicalcompound [III] for diastolic impairment, cardiac failure due todiastolic dysfunction, and reinforcement of diastolic function.

EXAMPLE 5 Experiment 3. The Effect of Coronary Relaxation from theFormula [III] or [IV] of the Present Invention

Porcine heart was purchased without regard of gender. The heart wascarried in steep, cool Krebs-Henseleit solution, filled with 95%bubbling oxygen (O₂) gas and bicarbonate (CO₂) and the left anteriordescending coronary artery of 2.5-3 mm diameter was removed. The arterywas steeped in the same nutrition solution overnight in a refrigeratorand the next day a specimen from a short strip removal in theendothelium (open ring) of width 3 mm was obtained. The specimen washanged in 10 ml of the organ bath filled with Krebs-Henseleit solution,95% bubbling oxygen (O₂) and bicarbonate (CO₂) at 37° C. One side wasfixed and the other side was connected to the isometric transducer(T7-8-240, T7-30-240, Olientic) and the change of tension on theamplifier was used for tension recording. After confirming the state for120 minutes under 1.5 g loading, KCl (40 mM) was added. When thecontraction reached a maximum, KCl was washed out. This wash-out wasrepeated 4 times during the course of 15 minutes. After the stablecontraction of KCl was obtained, KCl (30 mM) dissolved in saline wasadded. The compound [III] or [IV] dissolved in dimethysulfoxide (DMSO)was cumulatively added at 0.01-100 μM after obtaining the continuouscontraction. The Krebs-Henseleit solution without the compounds servedas the control.

Result: The effect of coronary relaxation was 0% in the control.However, the compound of the present invention [III] or [IV] indicatedthe effect of coronary relaxation of porcine heart dose-dependently.Data before administration was set at 100% and the data of each afteradministration was calculated as a percentage change from beforeadministration, with the concentration of chemical compound inducing 50%of relaxation (EC₅₀%) at 42 μM and 100 μM with compound [III] and [IV],respectively.

EXAMPLE 6 Experiment 4. Reducing Effect for the Contractility in theFormula [III] or [IV] of the Present Invention

Male guinea pigs, SLC-Hartley strain, weighing 900-1200 g were used inthis experiment. After bruising the head, animals were bled to death byperforming incisions to the carotid artery. Animal chests were thenopened and hearts were removed. Right atriums were removed from theventricle and a specimen of the right atrium was prepared. The specimenwas hanged in 20 ml of the organ bath with full Krebs-Henseleitsolution, 95% bubbling oxygen (O₂) and bicarbonate (CO₂) at 31° C. Oneside of specimen was fixed and the other side of it was connected to theisometric transducer (TB-651-T: Nihon-Koden Indust.). The beating rateof the spontaneous contraction of the specimen was recorded by therecorder (RECTIGRAPH-8K Nihon Electro Sanei) to evaluate thepharmacological agent. After confirming a stable state for 60-90 minutesunder loading of 0.5-1.0 g, the effect of the invention formula [III] or[IV] dissolved by dimethysulfoxide (DMSO) was evaluated to beadministered cumulatively at 0.01-100 μM. In the control group, theKrebs-Henseleit solution was used without the test compound. The databefore administration was set at 100% and the concentration inhibiting50% of the maximum contraction (IC₅₀ value) was investigated.

Result: In the control group, the inhibition of spontaneous contractionwas 9%. The formula [III] or [IV] of the present invention has indicatedan effect of inhibition to the right atrium in the guinea pigdose-dependently. The maximum value of contraction width beforeadministration was set at 100% and the concentration of 50% inhibition(IC₅₀) of the invention formula [III] or [IV] was 36 μM and 110 μM,respectively.

EXAMPLE 7 Experiment 5. Reducing Effect for the Heart Rate in theFormula [III] or [IV] of the Present Invention

Male guinea pigs weighing 900-1200 g were used in this experiment. Afterbruising the head, animals were bled to death by performing incisions tothe carotid artery. Animal chests were then opened and hearts wereremoved. The right atrium was removed from the ventricle and a specimenof the right atrium was prepared. The specimen was hanged in 20 ml ofthe organ bath with full Krebs-Henseleit solution 95% bubbling oxygen(O₂) and bicarbonate (CO₂) at 31° C. One side of the specimen was fixedand the other side of it was connected to the isometric transducer(TB-651-T: Nihon-Kohden Indust.). The beating rate of the spontaneouscontraction of the specimen was recorded by the recorder (RECTIGRAPH-8KNihon Electro Sanei). The effect of the formula [III] or [IV] of thepresent invention dissolved in dimethysulfoxide (DMSO) was evaluated forcumulative administration between 0.01-100 μM.

Results: In the control group, the right atrium contraction rate wasunable to be reduced. In the formula [III] and [IV] of the presentinvention, the right atrium contraction rate per minute of the guineapig was reduced dose-dependently. The 50% inhibition of maximumcontraction, set to 100% before administration (IC₅₀), was 35 μM and 110μM with compounds [III] and [IV], respectively.

From the results of 3 experiments, there have been discoveries that theinvention formula [III] or [IV] has the effect to dilate the coronaryvessels, reduce cardiac contraction and decrease heart rate.

EXAMPLE 8 Experiment 6. Comparison of Heart Rate, LV Pressure and LVDiastolic Function Between the Compound [III] and [II] of the PresentInvention (R═H) Experimental Method

Male Wistar rats weighing 280-300 g were bred. After one week, animalswere anesthetized with 3% isoflurane inhalation and respiration wassubsequently controlled with an artificial ventilator using 1.7%isoflurane for maintained anesthetization. A micronanometer-tippedpressure catheter (2F, Millar Instruments) was inserted from the rightcommon carotid artery into the left ventricle (LV) and a polyethylenecatheter (SP10) for solution injection was inserted from the rightfemoral vein and the compounds [III] and [II] (R═H) were injected. Afterconfirming stable hemodynamics for 10 minutes, heart rate, LV pressure,and maximal negative first derivative of LV pressure (−dP/dt) wereinvestigated continuously. Each compound [III] or [II] was infused at0.3 mg/kg/min for 5 minutes. Four rats in each group were evaluated. Thesolvent used consisted of 0.05% citric acid and 5% sorbitol. Eachparameter before and after 5 minutes of administration was determinedfor 20 heart beats. The results are presented in FIGS. 1, 2 and 3.

1) Effect of the Chemical Compounds [III] and [II] of the PresentInvention (R═H) for the Heart Beat

Heart rate (beat/min) was 361.7±26.5 before administration of thecompound [III] of the present invention and 360.9±29.1 afteradministration, indicating an unrecognizable change. For the othercompound, heart rate (beat/min) was 370.1±18.9 before administration ofthe compound [II] (R═H) and was significantly decreased to 320.2±24.2after the administration (FIG. 1). There are indications of differentpharmacological effects for heart rate between the chemical compounds[III] and [II] of the present invention (R═H).

2) Effect of the Compound [III] and [II] (R═H) for the LV Pressure

LV pressure (mmHg) was 106.0±5.8 before administration of the compound[III] with a slight change to 106.3±5.5 after administration. LVpressure (mmHg) was 103.7±4.2 before administration of the compound [II](R═H) and was almost the same at 100.8±6.0 after administration (FIG.2).

3) Comparison of LV Diastolic Function Between the Compound [III] and[II] (R═H)

LV diastolic function (mmHg/sec) was −5631.4±395.9 before administrationof the compound [III] and significantly improved to −5982.6±520.1 afteradministration. For the other, LV diastolic function (mmHg/sec) was−5973.4±1121.3 before administration of the compound [II] (R═H) andsignificantly decreased to −5311.0±961.4 (FIG. 3).

From the results, the present invention chemical compound is able toimprove LV diastolic function compared to the basic compound [II].However, the basic compound [II] significantly reduced LV diastolicfunction. There are differences of pharmacological effects for bothchemical compounds.

As above, the S-oxide chemical compound indicating the present did notchange the heart rate and improved the cardiac diastolic function. Incontrast, that basic chemical compound [II] decreased the heart rate andreduced the cardiac function. It is clear that the present inventiondiffers from the basic compound [II] in pharmacological effects,specifically heart rate and cardiac diastolic function.

EXAMPLE 9 Experiment 7. Effect for the Hypertension of the InventChemical Compound [III] Experimental Method

Male Wistar rats weighing 260 g were anesthetized with 3% isofluraneinhalation and respiration was subsequently controlled with anartificial ventilator using 1.7% isoflurane for maintainedanesthetization. A micronanometer-tipped pressure catheter (2F, MillarInstruments) was inserted from the right common carotid artery into theleft ventricle (LV) and a polyethylene catheter (SP10) for solutioninjection was inserted from the right femoral vein and test solutionswere injected. After confirming stable hemodynamics for 10 minutes,norepinephrine (20 μg/kg/min) was infused for 10 minutes followed by theinfusion of the invention compound [III] (0.1 mg/kg/min) for 10 minutes.This invention compound [III] was infused three times with intervals of10 minutes each. LV pressure was determined for 20 heart beats beforeand after administration. The infusion speed of each solution was 16.6μL/min. The results are shown in FIG. 4. The LV pressure (mmHg) was189.2±14.0 before this invention compound [III] and significantlydecreased to 180.3±14.9 after administration (FIG. 4).

1. A 1,4-benzothiazepine-1-oxide derivative represented by the followingformula [I]:

(wherein R is a hydrogen atom or a hydroxyl group.) and apharmaceutically acceptable salt thereof.
 2. The1,4-benzothiazepine-1-oxide derivative according to claim 1, wherein thepharmaceutically acceptable salt of 1,4-benzothiazepine-1-oxidederivative is an oxalate.
 3. A pharmaceutical composition comprising the1,4-benzothiazepine-1-oxide derivative according to claim 1 thepharmacologically acceptable carrier.
 4. The pharmaceutical compositionaccording to claim 3, wherein the pharmaceutical composition is atreatment agent or a prophylactic agent for cardiac disease andhypertension.
 5. The pharmaceutical composition according to claim 4,wherein the cardiac disease is cardiac failure, angina pectoris, ormyocardial infarction.
 6. The pharmaceutical composition according toclaim 5, wherein the cardiac failure is due to LV diastolic impairmentof cardiac relaxation impairment.
 7. The pharmaceutical compositionaccording to claim 4, wherein the hypertension is due to the effect ofdecreasing blood pressure during high blood pressure.
 8. Thepharmaceutical composition according to claim 3, wherein thepharmaceutical composition is a treatment agent or a prophylactic agentfor myocardial relaxation impairments due to complications of ischemicheart disease, hypertension cardiac diseases, heart failure, atrialfibrillation, and ventricular arrhythmia, by promoting acceleration ofmyocardial relaxation without changing heart rate.
 9. The pharmaceuticalcomposition according to claim 3, wherein the1,4-benzothiazepine-1-oxide derivative or pharmaceutically acceptablesalts thereof is generated in vivo by administering a1,4-benzothiazepine derivative or a pharmaceutically acceptable saltthereof represented by the following formula [II]:

(wherein R is a hydrogen atom or a hydroxyl group.) to a subject as amaternal compound of the 1,4-benzothiazepine derivative represented bythe formula [I].
 10. A method of producing a 1,4-benzothiazepinederivative represented by the following formula [I]:

(wherein R is a hydrogen atom or a hydroxyl group.) and apharmaceutically acceptable salt thereof comprising a step by oxidizinga 1,4-benzothiazepine derivative represented by the following formula[II]:

(wherein R is a hydrogen atom or a hydroxyl group.)
 11. The method ofproducing a 1,4-benzothiazepine derivative according to claim 10,wherein the oxidation carry out in the presence of peracid as aoxidation agent.